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      Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis

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          Abstract

          Aims

          Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk irrespective of age, but the evidence is less strong for older patients.

          Methods and results

          This prespecified analysis from ODYSSEY OUTCOMES compared the effect of alirocumab vs. placebo in 18 924 patients with recent acute coronary syndrome (ACS) according to age. We examined the effect of assigned treatment on occurrence of the primary study outcome, a composite of coronary heart disease death, myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization [major adverse cardiovascular event (MACE)] and all-cause death. Relative risk reductions were consistent for patients ≥65 vs. <65 years for MACE [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.68–0.91 vs. 0.89, 0.80–1.00; P interaction = 0.19] and all-cause death [HR 0.77, 0.62–0.95 vs. 0.94, 0.77–1.15; P interaction = 0.46], and consistent for MACE when dichotomizing at age 75 years (HR 0.85, 0.64–1.13 in ≥75 vs. 0.85, 0.78–0.93 in <75, P interaction = 0.19). When considering age as a continuous variable in regression models, advancing age increased risk of MACE, as well as the absolute reduction in MACE with alirocumab, with numbers-needed-to-treat for MACE at 3 years of 43 (25–186) at age 45 years, 26 (15–97) at age 75 years, and 12 (6–81) for those at age 85 years. Although adverse events were more frequent in older patients, there were no differences between alirocumab and placebo.

          Conclusion

          In patients with recent ACS, alirocumab improves outcomes irrespective of age. Increasing absolute benefit but not harm with advancing age suggests that LDL-C lowering is an important preventive intervention for older patients after ACS.

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          Most cited references7

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          Knowledge Gaps in Cardiovascular Care of the Older Adult Population: A Scientific Statement From the American Heart Association, American College of Cardiology, and American Geriatrics Society.

          The incidence and prevalence of most cardiovascular disorders increase with age, and cardiovascular disease is the leading cause of death and major disability in adults ≥75 years of age; however, despite the large impact of cardiovascular disease on quality of life, morbidity, and mortality in older adults, patients aged ≥75 years have been markedly underrepresented in most major cardiovascular trials, and virtually all trials have excluded older patients with complex comorbidities, significant physical or cognitive disabilities, frailty, or residence in a nursing home or assisted living facility. As a result, current guidelines are unable to provide evidence-based recommendations for diagnosis and treatment of older patients typical of those encountered in routine clinical practice. The objectives of this scientific statement are to summarize current guideline recommendations as they apply to older adults, identify critical gaps in knowledge that preclude informed evidence-based decision making, and recommend future research to close existing knowledge gaps. To achieve these objectives, we conducted a detailed review of current American College of Cardiology/American Heart Association and American Stroke Association guidelines to identify content and recommendations that explicitly targeted older patients. We found that there is a pervasive lack of evidence to guide clinical decision making in older patients with cardiovascular disease, as well as a paucity of data on the impact of diagnostic and therapeutic interventions on key outcomes that are particularly important to older patients, such as quality of life, physical function, and maintenance of independence. Accordingly, there is a critical need for a multitude of large population-based studies and clinical trials that include a broad spectrum of older patients representative of those seen in clinical practice and that incorporate relevant outcomes important to older patients in the study design. The results of these studies will provide the foundation for future evidence-based guidelines applicable to older patients, thereby enhancing patient-centered evidence-based care of older people with cardiovascular disease in the United States and around the world.
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            No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: a meta-analysis of individual patient data

            Abstract Aims Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab. Methods and results Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57–2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32–2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with LDL cholesterol (LDL-C) levels <25 mg/dL (<0.65 mmol/L; n = 5/839; 0.6%; 0.5/100 patient-years) vs. ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-years). One patient (0.1%; ezetimibe-controlled pool) receiving alirocumab had a neurocognitive TEAE leading to discontinuation vs. two (0.2%) patients receiving placebo and three (0.4%) patients receiving ezetimibe. Neurocognitive TEAE incidence was also similar between alirocumab and controls when stratified by age. Conclusions Neurocognitive TEAE incidences were low (≤1.2%), with no significant differences between alirocumab vs. controls up to 104 weeks. No association was found between neurocognitive TEAEs and LDL-C <25 mg/dL based on the completed Phase 2 and 3 trials examined, although long-term effects of very low LDL-C levels induced by PCSK9 inhibitors are currently unknown.
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              Real-life benefits of statins for cardiovascular prevention in elderly subjects: a population-based cohort study

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                Author and article information

                Journal
                Eur Heart J
                Eur. Heart J
                eurheartj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                21 June 2020
                16 November 2019
                16 November 2019
                : 41
                : 24 , Focus Issue on Lipids
                : 2248-2258
                Affiliations
                [1 ] Department of Cardiovascular Medicine, University Hospitals Leuven , Herestraat 49, 3000 Leuven, Belgium
                [2 ] Division of Cardiology, University of Colorado School of Medicine , Box B130, Aurora, CO 80045, USA
                [3 ] Duke Clinical Research Institute, Division of Cardiology, Duke University Medical Center , 200 Morris Street, Durham, NC 27701, USA
                [4 ] Department of Cardiology, Amphia Ziekenhuis Molengracht , 4818 CK Breda, Netherlands
                [5 ] Department of Medicine, Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School , 75 Francis Street, Boston, MA 02115, USA
                [6 ] Division of Cardiovascular Disease, University of Alabama at Birmingham , Birmingham, AL, USA
                [7 ] General Clinical Research Center and Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University , Shih-Pai Road, 11217 Taipei, Taiwan
                [8 ] Department of Internal Medicine, Cardiology, Alberto Sabogal Sologuren , ESSALUD, Jirón Colina 1081, Bellavista - Callao, Lima CA01, Peru
                [9 ] Cardiology Department, Instituto Cardiovascular de Rosario , Paraguay 160, Santa Fe, Rosario 2000, Argentina
                [10 ] Cardiology Department, Emergency Clinical Hospital of Bucharest , 8 Calea Floreasca, ET 6 014461 Bucharest, Romania
                [11 ] Canadian VIGOUR Centre, University of Alberta , 87 Ave NW, Edmonton, Alberta T6G 2E1, Canada
                [12 ] Division of Cardiology, St. Michael's Hospital, University of Toronto , 30 Bond Street, Toronto, Ontario M5B 1W8, Canada
                [13 ] Department of Cardiology, Leiden University Medical Center , PO Box 9600, 2300 RC Leiden, Netherlands
                [14 ] R&D Clinical Development , Sanofi, 1 avenue Pierre Brossolette, 91380 Chilly-Mazarin, France
                [15 ] Clinical Sciences - Cardiovascular & Metabolism Therapeutics, Regeneron Pharmaceuticals Inc. , 777 Old Saw Mill River Rd, Tarrytown, NY 10591, USA
                [16 ] Cardiovascular Institute, Cardinal Santos Medical Center , Wilson Street, San Juan, 1502 Metro Manila, Philippines
                [17 ] Downstate School of Public Health, State University of New York , 450 Clarkson Avenue, MS 43, Brooklyn, NY 11203 USA
                [18 ] Green Lane Cardiovascular Services , Auckland 20 City Hospital, Auckland, New Zealand
                [19 ] Department of Medicine III, Goethe University , Frankfurt am Main, Germany
                [20 ] Hopital Bichat, Universiteé de Paris, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Assistance Publique-Hopitaux de Paris , Paris, France
                [21 ] National Heart and Lung Institute, Imperial College , Royal Brompton Hospital, London, UK
                Author notes

                A complete list of the ODYSSEY OUTCOMES Committee investigators and contributors is provided in the Supplementary material online, Appendix .

                Corresponding author. Tel: +32 16 344 235, Fax: +32 16 344 240, Email: peter.sinnaeve@ 123456uzleuven.be
                Author information
                http://orcid.org/0000-0003-4716-5892
                http://orcid.org/0000-0002-1278-6245
                http://orcid.org/0000-0001-9456-850X
                http://orcid.org/0000-0003-1634-9402
                http://orcid.org/0000-0001-8068-2440
                http://orcid.org/0000-0002-8001-6795
                http://orcid.org/0000-0002-0046-0264
                http://orcid.org/0000-0001-7712-6750
                http://orcid.org/0000-0001-6896-2941
                Article
                ehz809
                10.1093/eurheartj/ehz809
                7308542
                31732742
                9acd1cf3-1949-418e-9838-e11c9a9e3d3e
                © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 26 September 2019
                : 12 October 2019
                : 29 October 2019
                Page count
                Pages: 11
                Funding
                Funded by: Sanofi; Regeneron Pharmaceuticals, Inc.;
                Funded by: Fondation Assistance Publique-Hôpitaux de Paris;
                Categories
                Fast Track Clinical Research
                Lipids

                Cardiovascular Medicine
                acute coronary syndrome,alirocumab,low-density lipoprotein cholesterol,age

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